Although muscle has its own progenitor cell for regeneration, lost muscle bulk and strength due to disease and injury are often never completely recovered. Therefore, treatments that can stimulate muscle growth and prevent muscle loss are likely to benefit a significant proportion of the population.
Increase in muscle growth, weight or function is important for treatment of deleterious conditions of the muscle, including, for example, muscle damage, muscle wasting, muscle degeneration, muscle atrophy or reduced rates of muscle repair. Such deleterious conditions of the muscle can result from normal conditions of use or trauma, or quite frequently, through chronic disease states.
In addition to the various muscle disorders that may require treatment, improving muscle to fat ratio so as to have a greater lean mass has been proposed to improve bone density. A correlation between lean mass and higher total body bone density has been shown in mice and in men. Conversely people with higher fat mass have been shown to have reduced bone density. Accordingly improving muscle to fat ratio may improve bone density and be particularly useful in treating bone disorders such as osteoporosis.
Additionally perfectly healthy people may be desirous of improved muscle form or function. It may be desirous to improve a person's weight carrying capacity, endurance, speed, or overall physique, all of which can be achieved by improving muscle mass or function. Additionally, it may be desirous to improve the recovery of muscle from injury or reduce the time a muscle needs to recovery from extended use, for example to reduce the time between training for athletes, thereby improving exercise tolerance.
In animal husbandry, such as involving animals as a food source, methods that increase the proportion and weight of muscle will greatly benefit the industry.
Given the importance of this field a great deal of research is ongoing to develop methods of controlling muscle development or growth. Much work has centred on finding inhibitors of myostatin, as mysotatin, in adults, is a negative regulator of muscle growth (i.e. it suppresses muscle growth).
Follistatin is a 35 kD glycoprotein that is synthesized in many tissues and acts as a binding protein for activin and other members of the TGFβ superfamily such as myostatin and some bone morphogenetic proteins. Follistatin is said to be one of several natural myostatin inhibitors, although its physiological role in muscle regulation is currently unknown. Nevertheless, administration of follistatin in muscle has been observed to lead to increased muscle mass, which is believed to be due to its binding and neutralization of myostatin. One of the difficulties of using follistatin as a therapeutic for increasing muscle growth is that follistatin binds other TGFβ ligands besides myostatin, for example, activin. Loss of activin activity in mice leads to numerous developmental defects and neonatal death. Activin also limits growth of many types of epithelial tissue, so that inhibition of activin action through administration of follistatin could lead to abnormal growth of these tissues and, eventually, to cancer.
There are currently no approved commercial pharmaceutical means for inhibiting myostatin activity that do not simultaneously alter activin activity. Myostatin antibodies have been developed which bind and neutralize myostatin without binding other TGFβ family ligands. However, antibodies may have certain drawbacks that might limit their utility as therapeutics for muscle wasting disorders and certainly the use of antibodies for muscle growth outside the therapeutic arena would be too costly to be commercially useful.
It is an aim of a preferred embodiment of the present invention to address one or more of the above issues and ideally provide a treatment for muscle disorders for improving muscle function, strength, weight and/or exercise tolerance.
All references, including any patents or patent applications, cited in this specification are hereby incorporated by reference. It will be clearly understood that, although a number of prior art publications are referred to herein, this reference does not constitute an admission that any of these documents forms part of the common general knowledge in the art.